Verbally expressed intentions of parasuicide: II. Prediction of fatal and nonfatal repetition

PURPOSE: To observe the immunological changes in epiretinal membranes from the patients with proliferative vitreoretinopathy (PVR). METHODS: Twelve samples of epiretinal membranes obtained during vitreous surgeries for PVR were examined by direct and indirect immunofluorescein histochemistry. RESULTS: The cellular membranes in 8 cases were composed of retinal pigment epithelial cells, fibroblast-like cells, macrophages and collagen. Positive stainings of IgG, C3+ collagen type III and macrophage-marker Ki-M7 (CD68) was seen in the membranes. CONCLUSION: The results indicate that humoral immune components and macrophages may play an important role in the development of epiretinal membrane formation.     

Basic fibroblast growth factor mRNA, bFGF peptide and FGF receptor in epiretinal membranes of intraocular proliferative disorders (PVR and PDR)

Basic fibroblast growth factor (bFGF) has been shown to be involved in epiretinal membrane formation in proliferative vitreoretinal disorders. However, up to now, little knowledge exists; as to the actual cellular source of this potent mitogen. We examined 20 epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) (n = 12) and proliferative vitreoretinopathy (PVR) (n = 8) for the presence of bFGF peptide, fibroblast growth factor receptor-1 (FGFR-1) and bFGF messenger ribonucleic acid (mRNA). Using a specific antibody, we detected bFGF peptide in most (8/10) examined PDR membranes and in all (8/8) PVR membranes. Moreover, we found positive staining for the corresponding receptor. Local production of bFGF in epiretinal membranes was confirmed by nonisotopic in situ hybridisation for bFGF mRNA in some (4/7) examined PDR membranes and some (3/4) examined PVR membranes. All membranes which contained bFGF mRNA were also positive for bFGF peptide. In conclusion, bFGF is produced and stored in epiretinal membranes. Together with the corresponding receptor, bFGF may play a role in the auto- and paracrine control of the proliferative processes at the vitreoretinal interface.     

Vitamin E inhibits retinal pigment epithelium cell proliferation in vitro

Retinal pigment epithelium (RPE) cells migrating through the damaged retina play an important role in the pathogenesis of proliferative vitreoretinopathy (PVR). We found that alpha-tocopherol (vitamin E) inhibits proliferation of human RPE in culture without exerting cytotoxic effects. Maximal inhibition was achieved with 100 microM alpha-tocopherol. Our result could explain the observation that vitamin E supplements have an adverse effect on light-damaged retina and on the course of retinitis pigmentosa. Since it has been shown that supplemental oral administrations of vitamin E can raise the RPE concentration of alpha-tocopherol well above 100 microM and supplementation is not associated with any clinical relevant adverse effect, we believe that vitamin E could be beneficial in the treatment of PVR.     

Inhibition of experimental proliferative vitreoretinopathy by retroviral vector-mediated transfer of suicide gene. Can proliferative vitreoretinopathy be a target of gene therapy?

PURPOSE: To determine the potential of somatic gene transfer as a treatment for proliferative vitreoretinopathy (PVR), experimental PVR was induced in rabbits by intraocular injection of fibroblasts bearing the herpes simplex virus thymidine kinase (HStk) gene. These transduced cells should be susceptible to cytotoxicity by exposure to ganciclovir (GCV). MATERIALS AND METHODS: Rabbit fibroblasts were transduced with retroviral vectors bearing an HStk gene. Proliferative vitreoretinopathy was induced by injection of 5 x 10(4) normal or HStk gene-transduced fibroblasts (HStk fibroblasts) into rabbit eyes. Ganciclovir (100 micrograms per eye) or saline was injected into the vitreous on days 0 and 4. Experimental animals were divided into three groups: group A received HStk fibroblasts with GCV; group B, normal fibroblasts with GCV; group C, HStk fibroblasts with saline. Proliferative vitreoretinopathy also was induced in several other groups of eyes, some receiving GCV and different proportions of HStk fibroblasts to normal fibroblasts, others receiving only normal fibroblasts and GCV. The eyes were examined by indirect ophthalmoscopy on days 4, 7, 14, and 28, and PVR was classified into six stages (0-5). RESULTS: Proliferative vitreoretinopathy was induced and progressed over time in each group. On day 28, PVR was most severe in animals in group B (average stage, 4.6) and group C (average stage, 4.4). Proliferative vitreoretinopathy was inhibited in group A (average stage, 1.0). The groups that received mixed injection of HStk fibroblasts and normal fibroblasts had intermediate PVR. Results of histologic study showed no apparent toxic or pathologic reaction in the retinochoroidal tissue of group A animals. CONCLUSIONS: Severity of experimental PVR clearly was reduced by transfer of the HStk gene and administration of GCV. This inhibitory effect also was produced by a combination of 10% HStk fibroblasts and 90% normal fibroblasts, indicating a significant bystander effect. These data suggest the potential of somatic gene therapy for the treatment of PVR.     

Radiation response of porcine RPE cells in vitro

PURPOSE: To investigate the antiproliferative effect of ionizing radiation on retinal pigment epithelial (RPE) cells that are supposed to play a major role in the pathogenesis of proliferative vitreoretinopathy (PVR). METHODS: RPE cells from pig eyes were irradiated with doses ranging from 4 to 16 Gy (1 Gray = 1 Joule/kilogram). Cells were counted at 1, 2, 3, and 4 weeks (Experiment 1) or 1, 2, 4, and 6 weeks (Experiment 2) after treatment. In Experiment 3, cells were trypsinized 24 h after radiation and seeded again. Colonies were counted 10 days later, and the surviving fraction was determined. RESULTS: The numbers of cells and colonies were inversely correlated to the doses applied. In Experiment 2, cell numbers of radiated cultures remained stable during the time of follow-up, whereas, in Experiment 1, significant proliferation occurred in treated cultures as well as in controls. This may be due to the higher growing rate that was found in the cultures of Experiment 2, compared to those of Experiment 1, at the time of radiation. In Experiment 3, a D0 value of 0.72 Gy was found. CONCLUSIONS: Proliferation of RPE cells can be suppressed by irradiation in a dose-dependent manner. Therefore, radiotherapy may be useful in the treatment of PVR. Its effect probably depends on the stage or activity of PVR at the time of radiation.     

Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma

Expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR, product of the met proto-oncogene) mRNA were examined by nonisotopic in situ hybridization in a spectrum of benign and malignant human breast tissues. mRNA for both HGFR and HGF was detected in benign ductal epithelium. Epithelial expression of HGF mRNA was particularly intense in regions of ductal epithelial hyperplasia. Positive expression of HGF (but not HGFR) mRNA was also found in adipocytes, endothelial cells, and to varying degrees in stromal fibroblasts. In 12 of 12 cases of ductal carcinoma in situ and infiltrating ductal carcinoma, carcinoma cells showed a heterogeneous pattern of expression for both HGFR and HGF mRNA. In infiltrating ductal carcinomas, intense expression of HGFR mRNA was not restricted to ductular structures but as also seen in non-duct-forming carcinoma cells. The same zones of the tumors (most commonly at the advancing margins) that expressed strongly HGFR mRNA often were also strongly positive for HGF mRNA, suggesting a possible autocrine effect. The expression pattern of HGFR protein in 25 cases including the same series of tissues used for in situ hybridization analysis was similar to that of HGFR mRNA, as determined by an immunoperoxidase technique. The finding that HGFR is expressed by both benign and malignant epithelium, and its not restricted to duct-forming structures, suggests that, although the potential for HGF/HGFR binding is maintained in malignancy, the response to ligand binding at the level of the receptor or the cellular response to receptor activation may change at some point during progression.     

The effectiveness of modified ingram therapy compared with severity of psoriasis

PURPOSE: This study investigated the pathogenesis of tractional retinal detachment associated with proliferative vitreoretinopathy in an experimental model, using immunohistochemical staining. METHODS: To produce tractional retinal detachment in rabbit eyes, homologous cultured fibroblasts obtained from the gluteal muscle fascia were injected intravitreously. Right eyes of 20 rabbits in the study group, and 7 rabbits in the control group were followed for 26 days at weekly intervals with indirect ophthalmoscopy and fundus photographs. RESULTS: During the follow-up period grade III tractional retinal detachment developed in 11 eyes, grade II in six, and grade 1 in three eyes. The spindle-shaped cells contributed predominantly to the development of epiretinal membrane, and a smaller number of round small and large cells. In 10/17 grade II and III eyes, spindle-shaped cells had vimentin, 7/10 had actin, 5/17 had GFAP, 4/17 had S-100 protein immunoreactivity. Round small and large cells expressed S-100 protein, GFAP and actin in 5/17 eyes. Epiretinal membrane appeared to be formed by spindle-shaped fibroblast-like cells and small and large round glia-like cells. Actin positivity of spindle-shaped and round cells was taken as a marker of contractile elements of the cells and their locomotional features. CONCLUSIONS: These features are believed to be involved in contraction of the membrane and retinal detachment.     

Results of vitreous surgery for proliferative vitreoretinopathy

During the past four years, we performed vitreous surgery on 73 eyes with rhegmatogenous retinal detachments complicated with severe proliferative vitreoretinopathy (PVR). We analyzed the surgical outcome of PVR according to the revised classification of PVR Grade C (1991). After a mean follow-up period of 19 months, the retinas were successfully reattached in 62 of 73 eyes (85%). The reattachment rate in the eyes with only posterior proliferation was high (96%), regardless of the extent of posterior proliferation. However, the reattachment rate in the eyes associated with anterior proliferation was markedly low (57%), depending on the extent of anterior proliferation. Among 62 eyes with successfully reattached retinas, 39 eyes (63%) had an improved postoperative visual acuity. These results demonstrated that the eyes with anterior PVR have a worse reattachment rate than the eyes with only posterior PVR. Using the revised classification of PVR, we were able to analyze the surgical outcome of PVR which could not be classified by the old classification.     

Dietary intake and adequacy of vitamin K

OBJECTIVE: To determine how often the fellow eyes of patients with proliferative vitreoretinopathy (PVR) harbor a vision-threatening condition at presentation; to determine how often the fellow eyes of patients with PVR develop vision-threatening conditions; and to determine how often the fellow eyes of patients with PVR lose vision. DESIGN: A retrospective case review design was used. PARTICIPANTS: Two hundred and forty-nine patients with PVR were studied. INTERVENTION: The authors observed the fellow eye of eyes with PVR for vision-threatening pathology. MAIN OUTCOME MEASURES: The primary anatomic endpoint of this study was the detection of vision-threatening pathology in the fellow eye of patients with PVR. Secondary outcome measures included the development of visual loss in the fellow eye. RESULTS: A wide variety of vision-threatening conditions were diagnosed in the fellow eyes of patients with PVR. Of patients meeting entry criteria with reliable follow-up data, greater than 50% of fellow eyes demonstrated vision-threatening pathology at some point during follow-up. CONCLUSIONS: Patients who develop PVR in one eye are at considerable risk for developing vision-threatening pathology or vision-damaging conditions in the fellow eye. This information should be carefully considered when making surgical decisions in patients facing PVR surgery.     

Proadrenomedullin N-terminal 20 peptide inhibits aldosterone secretion of human adrenocortical and Conn''s adenoma cells: comparison with adrenomedullin effect

Hepatocyte growth factor (HGF) is normally expressed by mesenchymal cells while its receptor, c-Met, is expressed in epithelial cells. Since HGF is critically involved in epithelial-mesenchyme interactions and the retinal pigment epithelium (RPE) is present at the interface between the retina and choroid, this study was initiated to determine whether the RPE expresses or responds to HGF in vitro. Cultured adult and fetal human RPE expressed mRNA for HGF and c-Met by RT-PCR. ELISA assay demonstrated the secretion of HGF into RPE culture supernatants. Tyrosine phosphorylation of c-Met was constitutively found in 72 hour RPE cultures and could be rapidly induced in serum-starved cells by concentrated RPE supernatants. HGF was mitogenic for cultured RPE (100 ng/ml.) and stimulated their chemotaxis (maximal response at 50 ng/ml). RPE are one of only a very limited number of epithelia that express both HGF and its receptor, suggesting the possibility of an autocrine action for this growth factor.     

Comparative study of incomplete posterior vitreous detachment as a risk factor for proliferative vitreoretinopathy

BACKGROUND: Abnormal vitreoretinal relationships have recently been implicated in many vitreoretinal disorders. Sites of abnormal vitreoretinal adherences are likely to exist in eyes predisposed to rhegmatogenous retinal detachment (RD), causing either retinal tears or incomplete posterior vitreous detachment (PVD). The present study was designed in two parts to identify the risk for preoperative and postoperative proliferative vitreoretinopathy (PVR) due to incomplete PVD. METHODS: We prospectively evaluated the vitreoretinal relationships using high-resolution kinetic echography in 102 consecutive eyes of 100 patients with rhegmatogenous RD. In the first part, a case-control study was conducted to compare the vitreous status in patients with preoperative PVR (cases) with that in patients with non-PVR-complicated RD (controls). During the second part, patients with noncomplicated RD (65 eyes) who were operated on by a simple retinal attachment procedure were followed up for a mean period of 6.6 months to compare the recurrence of RD due to postoperative PVR according to their vitreous status. RESULTS: Patients with PVR on study entry had a higher prevalence of partial PVD (28 of 32 eyes, 87%) than did controls (25 of 70 eyes, 35%). The statistical significance of this difference was independent of all other variables studied. After a mean follow-up period of 6.6 months, the incidence of recurrence of RD associated with postoperative PVR was 33% in the eyes with incomplete PVD, compared with 4.9% in the eyes without incomplete PVD. CONCLUSIONS: Our results support the notion that the occurrence of incomplete PVD in RD is a significant risk factor for preoperative and postoperative PVR.     

Migration of retinal pigment epithelium cells in vitro is regulated by protein kinase C

The migration of retinal pigment epithelial (RPE) cells is an important step in various pathologic conditions, including subretinal neovascularization (SRN) and proliferative vitreoretinopathy (PVR). Therefore, elucidation of the mechanism of RPE migration may be useful in devising effective treatment for these disorders. Since protein kinase C (PKC) has been shown to regulate the migration of other cell types, we studied the effects of PKC agonists and antagonists on RPE migration. We used an in vitro wound healing model in which a small area of a confluent monolayer of bovine RPE cells was denuded with a razor blade. The cultures were subsequently incubated with agents known to stimulate [phorbol 12-myristate 13-acetate (PMA)] or inhibit (calphostin C, staurosporine) PKC. After 20 hr, migration was measured as the number of cells that had entered the denuded area. We also measured the translocation of PKC from the cytosol to the membrane in order to determine the activation or inhibition of PKC by PMA and calphostin C in the cells. The phorbol ester PMA stimulated migration by 41%, and calphostin C and staurosporine inhibited migration by 38% and 31%, respectively, in a medium supplemented with 10% serum. To determine the requirement for serum in this modulation, we also measured the effects of PMA and calphostin C on RPE migration in serum-free medium. Under these conditions, basal migration was greatly decreased, but PMA stimulated migration by 177% and calphostin C inhibited migration by 93%. Since PKC modulation is known to induce the proliferation of cells, we also tested the effects of these agents on growth-inhibited migration by pretreating the cells with the antiproliferative drug mitomycin C. We found that modulation of PKC under these conditions equally affected growth-inhibited and growth-dependent migration. Therefore, based on the increase in RPE migration induced by a PKC agonist, and the decrease in migration caused by PKC antagonists, it is suggested that PKC-mediated signal transduction plays a crucial role in RPE cell migration. This knowledge may be useful in devising effective treatments for SRN and PVR.     

Intercellular adhesion molecule-1 in proliferative vitreoretinopathy

PURPOSE: To measure vitreous levels of the soluble intercellular adhesion molecule (sICAM-1) in eyes with rhegmatogenous retinal detachment (RRD) complicated or uncomplicated by proliferative vitreoretinopathy (PVR) to investigate whether levels of this molecule related to history of previous retinal surgery or to the duration and severity of PVR. METHODS: The authors measured vitreous sICAM-1 by enzyme-linked immunosorbent assay in 28 eyes with PVR and 35 eyes with uncomplicated RRD. Vitreous from 10 eyes with macular holes and from 12 cadaveric eye donors were used as control specimens. RESULTS: Vitreous sICAM-1 levels were higher in the group with RRD complicated by PVR as a whole than in the group with RRD alone or in the control groups. In patients with no previous retinal surgery, there was no difference in vitreous sICAM-1 levels between the groups with RRD alone and RRD complicated by PVR. However, in patients who had undergone previous external surgery, those with PVR showed higher levels of vitreous sICAM-1 than those with RRD alone. In PVR, raised levels of sICAM-1 were associated preferentially with a history of previous vitrectomy as well as with a longer duration of the condition, although these levels were not related to the grade of PVR. In eyes with RRD alone, the levels of sICAM-1 were not enhanced with the duration of the detachment. Despite showing high vitreous levels of sICAM-1, patients with PVR did not exhibit increased serum levels of this adhesion molecule. CONCLUSIONS: The current observations suggest that those persons in whom PVR develops may have an impairment of the mechanisms that control the inflammatory response to retinal trauma. Persistently raised vitreous levels of sICAM-1 point to the continued operation of cytokine-mediated vascular reactions at the blood-retinal barrier.     

Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy: results of a multicenter clinical trial. Daunomycin Study Group

PURPOSE: To assess the efficacy and safety of adjunctive daunorubicin during vitrectomy surgery in eyes with idiopathic proliferative vitreoretinopathy (PVR). METHODS: Two hundred eighty-six eyes (286 patients) with stage C2 (Retina Society Classification, 1983) or more advanced preoperative PVR in which surgery with silicone oil was planned were enrolled in a multicenter, prospective, randomized, controlled clinical trial. Standardized surgery plus adjunctive daunorubicin perfusion was compared with surgery alone. Outcomes assessed were retinal attachment without additional vitreoretinal surgery 6 months after standardized surgery, number of and time until vitreoretinal reoperations within 1 year of standardized surgery, and change in visual acuity 1 year after standardized surgery, evaluated by photodocumentation, number of reoperations, and measurement of best-corrected visual function. Outcomes were determined 6 months after operation and reevaluated after 1 year of follow-up. RESULTS: Six months after standardized surgery, complete retinal reattachment without additional vitreoretinal surgery was achieved in 62.7% (89/142) of eyes in the daunorubicin group vs 54.1% (73/135) in the control group (P = .07, one-sided). However, in the daunorubicin group, significantly fewer vitreoretinal reoperations were performed within 1 year postoperatively (P = .005, one-sided) to achieve the same overall 1-year retinal reattachment rate (80.2% [105/131] vs 81.8% [103/126]). The rate of patients with no vitreoretinal reoperations was 65.5% (95/145) in the daunorubicin group vs 53.9% (76/141) in the control group. There was no difference in the best-corrected visual acuity. No severe adverse effect related to daunorubicin was identified. CONCLUSIONS: Although the rate of anatomic success after 6 months failed to show significance, some benefit of the adjunctive treatment exists, especially a tendency toward increased rate of reattachment and a significant reduction in the number of reoperations. This shows that human PVR is amenable to pharmacologic treatment.     

Scaling of the limb long bones to body mass in terrestrial mammals

In their normal state, RPE cell are strongly adherent to Bruch's membrane. Certain pathological conditions such as retinal detachment cause an injury-type response (probably augmented or induced by the local accumulation of a variety of substances which modulate cell behaviour) in which RPE begin to dissociate from the membrane. This RPE-Bruch's membrane separation may be mediated by proteins with counter-adhesive properties and proteolytic enzymes, partly derived from the RPE themselves. Concomitant with the RPE disassociation, the cells begin to lose tertiary differentiation characteristics and gain macrophage-like features. When the "free" RPE arrive at the surface of the neuroretina, they may attach to or create a provisional matrix. Some of the cells adopt a fibroblast-like phenotype. This phenotype is similar to that of the dermal fibroblast during cutaneous wound repair and the fibroblastic RPE synthesise the types of matrix components found in healing skin wounds. Many of these molecules in turn further modulate the activities of the cells via several families of cell surface receptors, while the RPE continue to remodel the new matrix with a range of proteolytic enzymes. The resulting tissue (or membrane) has many of the features of a contractile scar and is the hallmark of the condition known as proliferative vitreoretinopathy (PVR). Thus the development of PVR, and the resulting tractional distortion of the neuroretina, appears to be dependent on RPE-matrix interactions. The interactions present a number of potential therapeutic targets for the management of the disorder.     

Preoperative vitreous hemorrhage associated with rhegmatogenous retinal detachment: a risk factor for postoperative proliferative vitreoretinopathy?

BACKGROUND: We conducted a prospective clinical study to elucidate the role of preoperative vitreous hemorrhage in the development of postoperative proliferative vitreoretinopathy (PVR) in primary rhegmatogenous retinal detachment. MATERIALS AND METHODS: We prospectively evaluated 409 eyes of 390 patients affected by primary rhegmatogenous retinal detachment referred before any failed attempt to reattach the retina. Single and multiple logistic regression analysis were used to test 14 categories of variables. RESULTS: Postoperative PVR occurred in 48 (11.7% of 409 eyes). Postoperative PVR developed in 41 (11.8%) of the 347 eyes with no preoperative vitreous hemorrhage, and 7 (11.3%) of the 62 eyes with preoperative vitreous hemorrhage (P = 0.90). The results of multiple logistic regression analysis showed that only four variables were significant factors which had independently and jointly an effect on the risk of postoperative PVR: (1) 90 degrees or greater circumferential extent of the retinal tears; (2) preoperative PVR grade B; (3) preoperative PVR grade C-D; and (4) the use of cyrotreatment as the method of retinopexy. CONCLUSION: With the surgical techniques currently used, mild preoperative vitreous hemorrhage is not an independent risk factor for postoperative PVR in primary rhegmatogenous retinal detachment. The role of moderate and severe vitreous hemorrhage remains to be fully evaluated in a larger series of eyes.     

Gene expression of HGF and its receptor in experimental hepatomas

OBJECTIVE: To understand the regularity of changes of gene expression about HGF and its receptor (HGFR) in experimental hepatomas model of Wistar rats and the relationship between this change and tumor biological behaviour. METHODS: The gene expression of HGF and HGFR in the canceration course of rats was determined by using experimental hepatomas model of Wistar rats established by diethylnitrosamine (DENA), with digoxigenin-labled probe. RESULTS: The positive expression of HGF and HGFR was found in rats liver tissues, but it was different in distinct stages. The positive expression of HGF was the highest in precirrhosis stage, and next in the cirrhosis stage. The canceration stage was the same as in the normal group. The positive expression of HGFR was gradually increased following the canceration course and the canceration stage was the highest, but we didn't find the expression of HGFR in normal liver tissues. CONCLUSIONS: There are close relations between the gene expression of HGF and HGFR and evolution course during the canceration of rats liver. HGF and HGFR systems play an important role in regulating tumor growth and metastasis.     

Silicone assisted, argon laser confinement of recurrent proliferative vitreoretinopathy related retinal detachment: a technique to allow silicone oil removal in problem eyes

AIMS/BACKGROUND: Recurrent peripheral retinal detachments may occur in eyes treated with vitrectomy and silicone oil for retinal detachments complicated by proliferative vitreoretinopathy (PVR). The aim of this study was to assess whether laser photocoagulation could be used in the presence of silicone oil to confine and stabilise recurrent PVR related peripheral retinal detachments enabling the timely removal of the oil. METHODS: 10 patients with recurrent peripheral retinal detachments after vitrectomy and silicone oil insertion were treated with posturing and subsequent focal argon laser to circumscribe the area of recurrent detachment. RESULTS: This technique alone was sufficient to limit the area of retinal detachment in seven of the cases. The remaining three cases required relieving retinotomies because of increasing retinal detachment despite the laser. In all 10 cases the silicone oil was later removed without progression of the detached areas. CONCLUSION: Silicone assisted argon laser 'confinement' can be effective in stabilising eyes with peripheral retinal detachments allowing the subsequent removal of silicone oil.